Histocompatibility-linked immune response (H-linked Ir) genes control the development of antibody responses and/or cellular immunity to numerous antigens in several species. The objectives of the proposed research are to identify and characterize the mechanism(s) by which H-linked Ir genes regulate antibody responses to the synthetic antigen L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) and insulin by inbred strains of mice. Already established and well-characterized tissue culture systems will be used to investigate critical factors in Ir gene regulation of antibody responses. The antibody responses that develop in cultures containing spleen cells or various combinations of purified macrophages, thymus-derived cells (T cells) and precursors of antibody-producing cells (B cells) from responder and nonresponder mice will be measured by a modification of the hemolytic plaque assay using GAT- or insulin-conjugated sheep erythrocytes as indicator cells. The specific aims of these experiments are to characterize the functional differences in antigen-specific helper and suppressor T cells and B cells from responder and nonresponder mice to determine whether H-linked Ir genes are structural genes that encode specific receptors or whether they are regulatory genes that function after antigen-receptor interaction. Identification and characterization of the H-linked Ir gene defect(s) in nonresponder mice will provide valuable insights into regulatory mechanisms in normal immune responses. These insights should lead to a better appreciation of mechanisms of disease processes with immunological components, to rational therapeutic measures to correct immunological imbalances and to the ability to predict immunological consequences of disease management.